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Stefanski AL, Dörner T, Kneitz C. [Influence of underlying disease and immunosuppression on the immunocompetence in inflammatory rheumatic diseases]. Z Rheumatol 2024; 83:87-97. [PMID: 37644129 DOI: 10.1007/s00393-023-01408-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2023] [Indexed: 08/31/2023]
Abstract
Patients with inflammatory rheumatic diseases have a higher risk of infections in comparison to the general population. For this patient group, in addition to cardiovascular diseases, infections play an important role with respect to morbidity and mortality. Even if it is difficult to make concrete statements with respect to individual diseases, it can be assumed that there is a lower risk of infections in inflammatory joint diseases in comparison to connective tissue diseases and vasculitides. The increased risk of infections is determined by multiple factors, whereby the underlying factors are classified into three main categories: patient-related factors (age, comorbidities, lifestyle), disease-related factors (immunological dysfunction as part of the disease pathophysiology) and drug-related factors (type and dosage of the immunosuppression and/or immunomodulation). An improved understanding of the complexity of these associations enables the optimization of treatment and disease control taking the individual risk factors into account, with the aim of a significant reduction in the risk of infections.
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Affiliation(s)
- A-L Stefanski
- Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland.
- Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Deutschland.
| | - T Dörner
- Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland
- Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Deutschland
| | - C Kneitz
- Rheumatologische Schwerpunktpraxis Schwerin, Schwerin, Deutschland
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Khoshbakht S, Başkurt D, Vural A, Vural S. Behçet's Disease: A Comprehensive Review on the Role of HLA-B*51, Antigen Presentation, and Inflammatory Cascade. Int J Mol Sci 2023; 24:16382. [PMID: 38003572 PMCID: PMC10671634 DOI: 10.3390/ijms242216382] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/04/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Behçet's disease (BD) is a complex, recurring inflammatory disorder with autoinflammatory and autoimmune components. This comprehensive review aims to explore BD's pathogenesis, focusing on established genetic factors. Studies reveal that HLA-B*51 is the primary genetic risk factor, but non-HLA genes (ERAP1, IL-10, IL23R/IL-12RB2), as well as innate immunity genes (FUT2, MICA, TLRs), also contribute. Genome-wide studies emphasize the significance of ERAP1 and HLA-I epistasis. These variants influence antigen presentation, enzymatic activity, and HLA-I peptidomes, potentially leading to distinct autoimmune responses. We conducted a systematic review of the literature to identify studies exploring the association between HLA-B*51 and BD and further highlighted the roles of innate and adaptive immunity in BD. Dysregulations in Th1/Th2 and Th17/Th1 ratios, heightened clonal cytotoxic (CD8+) T cells, and reduced T regulatory cells characterize BD's complex immune responses. Various immune cell types (neutrophils, γδ T cells, natural killer cells) further contribute by releasing cytokines (IL-17, IL-8, GM-CSF) that enhance neutrophil activation and mediate interactions between innate and adaptive immunity. In summary, this review advances our understanding of BD pathogenesis while acknowledging the research limitations. Further exploration of genetic interactions, immune dysregulation, and immune cell roles is crucial. Future studies may unveil novel diagnostic and therapeutic strategies, offering improved management for this complex disease.
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Affiliation(s)
- Saba Khoshbakht
- Koç University Research Center for Translational Medicine, Istanbul 34010, Turkey; (S.K.); (A.V.)
| | - Defne Başkurt
- School of Medicine, Koç University, Istanbul 34010, Turkey;
| | - Atay Vural
- Koç University Research Center for Translational Medicine, Istanbul 34010, Turkey; (S.K.); (A.V.)
- Department of Neurology, Koç University School of Medicine, Istanbul 34010, Turkey
| | - Seçil Vural
- Koç University Research Center for Translational Medicine, Istanbul 34010, Turkey; (S.K.); (A.V.)
- Department of Dermatology and Venereology, Koç University School of Medicine, Istanbul 34010, Turkey
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Al-Obeidi AF, Nowatzky J. Immunopathogenesis of Behçet's disease. Clin Immunol 2023; 253:109661. [PMID: 37295542 PMCID: PMC10484394 DOI: 10.1016/j.clim.2023.109661] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/31/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023]
Abstract
Behçet's disease (BD) is a multi-system inflammatory disorder with vasculitic features. It does not suit any of the current pathogenesis-driven disease classifications well, a unifying concept of its pathogenesis is not unanimously conceivable at present, and its etiology is obscure. Still, evidence from immunogenetic and other studies supports the notion of a complex-polygenic disease with robust innate effector responses, reconstitution of regulatory T cells upon successful treatment, and first clues to the role of an, as of yet, underexplored adaptive immune system and its antigen recognition receptors. Without an attempt to be comprehensive, this review aims to collect and organize impactful parts of this evidence in a way that allows the reader to appreciate the work done and define the efforts needed now. The focus is on literature and notions that drove the field into new directions, whether recent or more remote.
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Affiliation(s)
- Arshed F Al-Obeidi
- New York University Grossman School of Medicine, Department of Medicine, New York, NY, USA
| | - Johannes Nowatzky
- New York University Grossman School of Medicine, Department of Medicine, New York, NY, USA; New York University Grossman School of Medicine, Department of Pathology, USA; New York University Grossman School of Medicine, Department of Medicine, Division of Rheumatology, NYU Langone Ocular Rheumatology Program, New York, NY, USA; New York University Grossman School of Medicine, Department of Medicine, Division of Rheumatology, NYU Langone Center for Behçet's Disease, New York, NY, USA.
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Zou J, Li B, Li D, Bao HF, She CH, Ye JF, Cai JF, Guan JL. Comprehensive analysis of T-cell receptor repertoires reveals antigen-driven T-cell clusters in patients with Behçet's syndrome. Eur J Immunol 2023; 53:e2250181. [PMID: 36747316 DOI: 10.1002/eji.202250181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/23/2023] [Accepted: 01/31/2023] [Indexed: 02/08/2023]
Abstract
T lymphocytes are the major components of adaptive immunity in Behçet's syndrome (BS) pathology. However, the precise mechanism of T-cell-induced inflammatory condition remains to be determined. We applied bulk sequencing of the T-cell receptor (TCR) β chain in peripheral blood samples from 45 patients with BS and 10 healthy donors as controls. TCR repertoires in BS patients displayed more clonality and less diversity than in healthy donors. Male patients exhibited lower diversity metrics of TCR and had a larger proportion in the top 10 clones than females (p = 0.016). There were no TCR clonality differences in other clinical features, such as age, disease duration, organ involvement, disease severity, and activity. By "Grouping of Lymphocyte Interactions by Paratope Hotspots" (GLIPH2) for antigen prediction, we found distinct 2477 clusters of TCR-β sequences that potentially recognize similar antigens shared between BS patients. We observed clonal T-cell expansion in BS patients. Sexual differences in TCR clonal expansion and public TCR groups deserve further study to reveal the underline T-cell-mediated immunity in BS.
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Affiliation(s)
- Jun Zou
- Division of Rheumatology and Immunology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Bin Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University, Shanghai, China
| | - Dan Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University, Shanghai, China
| | - Hua-Fang Bao
- Division of Rheumatology and Immunology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Chun-Hui She
- Division of Rheumatology and Immunology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Jing-Fen Ye
- Division of Rheumatology and Immunology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Jian-Fei Cai
- Division of Rheumatology and Immunology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Jian-Long Guan
- Division of Rheumatology and Immunology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
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Zeng L, Meng WJ, Wen ZH, Chen YL, Wang YF, Tang CW. Management and outcomes of surgical patients with intestinal Behçet’s disease and Crohn’s disease in southwest China. World J Clin Cases 2021; 9:3858-3868. [PMID: 34141742 PMCID: PMC8180223 DOI: 10.12998/wjcc.v9.i16.3858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 03/01/2021] [Accepted: 04/06/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastrointestinal involvement in Behçet's disease (GIBD) and Crohn’s disease (CD) are inflammatory diseases sharing a considerable number of similarities. However, different from CD, the operative and postoperative management of GIBD remains largely empirical because of the lack of comprehensive treatment guidelines.
AIM To compare surgical patients with GIBD and those with CD in a medical center and identify notable clinical features and effective postoperative treatment for surgical patients with GIBD.
METHODS We searched patients diagnosed with CD and GIBD who underwent operations for gastrointestinal complications from 2009 to 2015 at West China Hospital of Sichuan University. A total of 10 surgical patients with GIBD and 106 surgical patients with CD were recruited. Information including demographic data, medication, and operative and postoperative parameters were collected and analyzed. As the incidence of surgical GIBD is low, their detailed medical records were reviewed and compared to previous studies. Moreover, the prognoses of CD and GIBD were evaluated respectively between groups treated with biological and non-biological agents.
RESULTS Indication for first surgery was often acute intestinal perforation for GIBD patients (7/10 vs 0/106, P < 0.001), whereas intestinal fistulae (0/10 vs 44/106, P = 0.013) and ileus (0/10 vs 40/106, P = 0.015) were the indications for surgical CD patients. Approximately 40% of patients with GIBD and 23.6% of patients with CD developed postoperative complications, 50% of patients with GIBD and 38.7% of patients with CD had recurrence postoperatively, and 40% (4/10) of patients with GIBD and 26.4% (28/106) of patients with CD underwent reoperations. The average period of postoperative recurrence was 7.87 mo in patients with Behçet's disease (BD) and 10.43 mo in patients with CD, whereas the mean duration from first surgery to reoperation was 5.75 mo in BD patients and 18.04 mo in CD patients. Surgical patients with GIBD more often used corticosteroids (6/10 vs 7/106, P < 0.001) and thalidomide (7/10 vs 9/106, P < 0.001) postoperatively, whereas surgical patients with CD often used infliximab (27/106), azathioprine, or 6-mercaptopurine (74/106) for maintenance therapy.
CONCLUSION Patients suffering GIBD require surgery mostly under emergency situations, which may be more susceptible to recurrence and reoperation and need more aggressive postoperative treatment than patients with CD.
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Affiliation(s)
- Li Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Jian Meng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zhong-Hui Wen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yi-Long Chen
- West China Biomedical Big Data Center, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Fang Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Cheng-Wei Tang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Cheon JH. Advances in Management of Intestinal Behçet's Disease: A Perspective From Gastroenterologists. JOURNAL OF RHEUMATIC DISEASES 2021; 28:4-16. [PMID: 37476392 PMCID: PMC10324954 DOI: 10.4078/jrd.2021.28.1.4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/09/2020] [Accepted: 08/10/2020] [Indexed: 07/22/2023]
Abstract
Intestinal Behçet's disease (intestinal BD) is a rare chronic inflammatory disorder of the intestine that is characterized by recurrent intestinal manifestations with other systemic features of BD. Intestinal BD is diagnosed when a typically shaped ulcer is observed in the gastrointestinal tract, and the clinical findings meet the diagnostic criteria for BD. Owing to the small number of patients, intestinal BD is easily underestimated. On the other hand, but it often requires surgical treatment because of severe complications, including intestinal perforations or massive bleeding. The same treatment strategies used for inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, are used for intestinal BD. 5-Aminosalicylic acids, corticosteroids, and immunomodulators are considered conventional therapies, but a considerable number of patients eventually become unresponsive to these pharmaceutical treatments. Recently, biologic agents, such as anti-tumor necrosis factor-alpha inhibitors, have also been suggested as a new treatment option for intestinal BD. This article reviews the pathogenesis and diagnosis of intestinal BD and the current treatment strategies that are expected to be useful for rheumatologic specialists.
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Affiliation(s)
- Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Deniz R, Tulunay-Virlan A, Ture Ozdemir F, Unal AU, Ozen G, Alibaz-Oner F, Aydin-Tatli I, Mumcu G, Ergun T, Direskeneli H. Th17-Inducing Conditions Lead to in vitro Activation of Both Th17 and Th1 Responses in Behcet's Disease. Immunol Invest 2017; 46:518-525. [PMID: 28414558 DOI: 10.1080/08820139.2017.1306865] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Interleukin-17 (IL-17) has been associated with the pathogenesis of various autoimmune/inflammatory diseases. The aim of this study was to investigate the expression of Th17-related immunity in an innate immunity-dominated vasculitis, namely Behcet's disease (BD). METHODS Peripheral blood mononuclear cells from 37 patients (age: 38.5 ± 9.8 years) with BD, and 25 healthy controls (HC) (age: 39.1 ± 9.3 years), were cultured in Th17-inducing conditions (IL-6, Phytohemagglutinin (PHA), IL-1β, and IL-23) for 6 days. Cultured cells were stained with CD4, CD8, CD3, TCR gamma/delta, CD19, interferon-γ (IFN-γ), and IL-17 antibodies to determine the intracellular cytokine secretion by flow cytometry. RESULTS IL-17 expression by CD8+ and γδ+ T cells was higher in BD compared to HC (p = 0.004, p = 0.003, respectively). No differences were observed between the groups in the IL-17 production by B cells. Under Th17-inducing conditions, production of IFN-γ by CD4+, CD8+, and γδ+ T cells was also higher in BD compared to HC (p < 0.05 in all). CONCLUSION Our results suggest that under Th17-stimulating conditions, T cells express both IL-17 and IFN-γ in BD. More prominent IL-17 and IFN-γ production by all lymphocyte subsets in BD might be associated with the increased innate responses, early tissue neutrophil infiltrations and late adaptive immunity in BD.
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Affiliation(s)
- Rabia Deniz
- a Department of Internal Medicine, School of Medicine , Marmara University , Istanbul , Turkey
| | - Aysın Tulunay-Virlan
- b Department of Immunology, School of Medicine , Marmara University , Istanbul , Turkey
| | - Filiz Ture Ozdemir
- b Department of Immunology, School of Medicine , Marmara University , Istanbul , Turkey
| | - Ali Ugur Unal
- c Division of Rheumatology, School of Medicine , Marmara University , Istanbul , Turkey
| | - Gulsen Ozen
- c Division of Rheumatology, School of Medicine , Marmara University , Istanbul , Turkey
| | - Fatma Alibaz-Oner
- c Division of Rheumatology, School of Medicine , Marmara University , Istanbul , Turkey
| | - Imren Aydin-Tatli
- b Department of Immunology, School of Medicine , Marmara University , Istanbul , Turkey
| | - Gonca Mumcu
- d Faculty of Health Science, Department of Health Informatics and Technologies, School of Medicine , Marmara University , Istanbul , Turkey
| | - Tulin Ergun
- e Department of Dermatology, School of Medicine , Marmara University , Istanbul , Turkey
| | - Haner Direskeneli
- c Division of Rheumatology, School of Medicine , Marmara University , Istanbul , Turkey
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Özdemir FT, Demiralp EE, Aydın SZ, Atagündüz P, Ergun T, Direskeneli H. Immune and inflammatory gene expressions are different in Behçet's disease compared to those in Familial Mediterranean Fever. Eur J Rheumatol 2017; 3:146-152. [PMID: 28149656 DOI: 10.5152/eurjrheum.2016.15099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 07/15/2016] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVE The immune classification of Behçet's disease (BD) is still controversial. In this study, we aimed to compare the immune/inflammatory gene expressions in BD with those in familial Mediterranean fever (FMF), an autoinflammatory disorder with innate immune activation. MATERIAL AND METHODS CD4+ T cells and CD14+ monocytes were isolated from the peripheral blood mononuclear cells of Behçet's disease patients (n=10), FMF (n=6) patients, and healthy controls (n=4) with microbeads, and then, the mRNA was isolated. The expressions of 440 genes associated with immune and inflammatory responses were studied with a focused DNA microarray using a chemiluminescent tagging system. Changes above 1.5-fold and below 0.8-fold were accepted to be significant. RESULTS In BD patients, in the CD4+ T-lymphocyte subset, interleukin 18 receptor accessory protein (1.7-fold), IL-7 receptor (1.9-fold), and prokineticin 2 (2.5-fold) were all increased compared to those in FMF patients, whereas chemokine (C-X3-C motif ) receptor-1 (CX3CR1) (0.7-fold) and endothelial cell growth factor-1 (0.6-fold) were decreased. In the CD14+ monocyte population, the V-fos FBJ murine osteosarcoma viral oncogene homolog (1.5-fold), Interleukin-8 (IL-8) (2.1-fold), and Tumor Necrosis Factor alpha (TNF-α) (1.8-fold) were all increased, whereas the chemokine (C-C motif ) ligand 5 (CCL5) (0.6-fold), C-C chemokine receptor type 7 (0.6-fold), and CX3CR1 (0.7-fold) were decreased, again when compared to those in FMF. Compared to healthy controls in the CD4+ T-lymphocyte population, in both BD and FMF patients, pro-platelet basic protein and CD27 had elevated expression. In BD and FMF patients, 24 and 19 genes, respectively, were downregulated, with 15 overlapping genes between both disorders. In the CD14+ monocytes population, chemokine (C-C motif ) receptor-1 (CCR1) was upregulated both in BD and FMF patients compared to that in the controls, whereas CCL5 was downregulated. CONCLUSION Immune and inflammatory gene expressions seem to be variable in both the innate (CD14+) and adaptive (CD4+) immune responses in BD and FMF patients compared to those in controls, suggesting differences in immune regulation between the two disorders.
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Affiliation(s)
- Filiz Türe Özdemir
- Department of Immunology, Marmara University School of Medicine, İstanbul, Turkey
| | - Emel Ekşioğlu Demiralp
- Department of Immunology, Marmara University School of Medicine, İstanbul, Turkey; Department of Immunology, Memorial Şişli Hospital, İstanbul, Turkey
| | - Sibel Z Aydın
- Department of Rheumatology, Marmara University School of Medicine, İstanbul, Turkey; Department of Rheumatology, Ottawa University School of Medicine, Ottawa, Canada
| | - Pamir Atagündüz
- Department of Rheumatology, Marmara University School of Medicine, İstanbul, Turkey
| | - Tülin Ergun
- Department of Dermatology, Marmara University School of Medicine, İstanbul, Turkey
| | - Haner Direskeneli
- Department of Rheumatology, Marmara University School of Medicine, İstanbul, Turkey
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Kim JH, Lee DW, Cho NC. The Efficacy of Infliximab in Refractory Uveitis. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2016. [DOI: 10.3341/jkos.2016.57.1.50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Joon Hyung Kim
- Department of Ophthalmology, Chonbuk National University Medical School, Jeonju, Korea
| | - Dong Wook Lee
- Department of Ophthalmology, Chonbuk National University Medical School, Jeonju, Korea
- Research Institute of Clinical Medicine, Chonbuk National University, Jeonju, Korea
- Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Korea
| | - Nam Chun Cho
- Department of Ophthalmology, Chonbuk National University Medical School, Jeonju, Korea
- Research Institute of Clinical Medicine, Chonbuk National University, Jeonju, Korea
- Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Korea
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Kim DH, Cheon JH. Intestinal Behçet's Disease: A True Inflammatory Bowel Disease or Merely an Intestinal Complication of Systemic Vasculitis? Yonsei Med J 2016; 57:22-32. [PMID: 26632379 PMCID: PMC4696957 DOI: 10.3349/ymj.2016.57.1.22] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Indexed: 12/18/2022] Open
Abstract
Behçet's disease (BD) is a multi-systemic inflammatory disorder of an unknown etiology and shows a chronic recurrent clinical course. When the disease involves the alimentary tract, it is called intestinal BD because of its clinical importance. Intestinal BD is more frequently reported in East Asian countries than in Western or Middle Eastern countries. While any part of the gastrointestinal tract can be involved, the most common location of intestinal BD is the ileocecal area. A few, large, deep ulcerations with discrete border are characteristic endoscopic findings of intestinal BD. Currently, there is no single gold standard test or pathognomonic finding of intestinal BD. However, recently developed novel diagnostic criteria and a disease activity index have helped in assessing intestinal BD. As intestinal BD shares a lot of characteristics with inflammatory bowel disease, including genetic background, clinical manifestations, and therapeutic strategies, distinguishing between the two diseases in clinical practice is quite difficult. However, biologic agents such as anti-tumor necrosis factor α antibody shows a considerable efficacy similar to inflammatory bowel disease cases. It is important to distinguish and treat those two disease entities separately from the standpoint of precise medicine. Clinicians should require comprehensive knowledge regarding the similarities and differences between intestinal BD and inflammatory bowel disease for making an accurate clinical decision.
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Affiliation(s)
- Duk Hwan Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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Rolla G, Guida G, Heffler E. Churg–Strauss syndrome: still a clinical challenge. Expert Rev Clin Immunol 2014; 3:833-7. [DOI: 10.1586/1744666x.3.6.833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Animal Models in Behçet's Disease. PATHOLOGY RESEARCH INTERNATIONAL 2012; 2012:273701. [PMID: 22482083 PMCID: PMC3316952 DOI: 10.1155/2012/273701] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Revised: 11/03/2011] [Accepted: 11/04/2011] [Indexed: 11/18/2022]
Abstract
Behçet's disease is a chronic, recurrent, multisystemic, inflammatory disorder affecting mainly the oral and urogenital mucosa and the uveal tract. Although the etiology and pathogenesis of Behçet's disease are unknown, numerous etiologies have been proposed, including environmental, infectious, and immunological factors; an autoimmune basis, characterized by circulating immune complexes and complement activation, has gained increasing acceptance. To test and understand immunopathogenesis of Behçet's disease, animal models were developed based on enviromental pollutants, bacterial and human heat shock protein derived peptides, and virus injections. Using these animal models separately and/or concurrently allows for a more effective investigation into Behçet's disease. Animal models developed in the last 10 years aim at the development of efficient and safe treatment options.
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Maldini C, Lavalley MP, Cheminant M, de Menthon M, Mahr A. Relationships of HLA-B51 or B5 genotype with Behcet's disease clinical characteristics: systematic review and meta-analyses of observational studies. Rheumatology (Oxford) 2012; 51:887-900. [PMID: 22240504 DOI: 10.1093/rheumatology/ker428] [Citation(s) in RCA: 131] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE To investigate comprehensively the relationships between Behçet's disease (BD) clinical features and HLA-B51 or HLA-B5 (HLA-B51/B5) status using meta-analyses. METHODS Relevant publications were identified by a systematic literature search. Eligible studies had to provide frequencies for one or more BD characteristics according to HLA-B51/B5 status. Pooled relative risks (RRs) were calculated by random-effects meta-analysis for those BD characteristics for which five or more relevant studies were identified. Between-study variability was assessed with I(2) and Q-statistics, and modelled using meta-regression. RESULTS Among the 859 publications evaluated, 72 (representing 74 study populations) met eligibility criteria. Pooled RRs (95% CIs) of the association of HLA-B51/B5 with the 14 analysed clinical characteristics were male sex 1.14 (1.05, 1.23); eye involvement 1.13 (1.06, 1.21); genital ulcers 1.07 (1.01, 1.14); skin involvement 1.10 (1.03, 1.16); erythema nodosum 1.11 (0.96, 1.29); pseudofolliculitis 1.07 (0.93, 1.23); positive pathergy test 1.05 (0.94, 1.17); joint involvement 0.94 (0.86, 1.04); neurological involvement 0.95 (0.71, 1.27); gastrointestinal involvement 0.70 (0.52, 0.94); thrombophlebitis 1.17 (0.77, 1.76); vascular involvement 1.00 (0.68, 1.47); chest involvement 1.55 (0.75, 3.20) and orchiepididymitis 1.13 (0.59, 2.15). For most of the analysed outcomes, between-study heterogeneity was low or absent and most of the meta-regression models were statistically non-significant. CONCLUSION The results of these meta-analyses showed that, in BD, HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin manifestations, and a decreased prevalence of gastrointestinal involvement.
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Affiliation(s)
- Carla Maldini
- Department of Internal Medicine, Hospital Saint-Louis, 1 avenue Claude-Vellefaux, 75475 Paris Cedex 10, France
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Abstract
PURPOSE OF REVIEW To alert physician to timely recognition and current treatment of recurrent hypopyon iridocyclitis or panuveitis in ocular Behçet disease (OBD). RECENT FINDINGS Interferon-α, rituximab, intravitreal triamcinolone, and biological response modifiers by tumor necrosis factor inhibitors such as infliximab and adalimumab are being used increasingly for the treatment of severe sight-threatening ocular inflammation including retinal vasculitis and cystoid macular edema (CME). SUMMARY Biological agents offer tremendous potential in the treatment of OBD. Given that OBD predominantly afflicts the younger adults in their most productive years, dermatologist, rheumatologist, internist, or general practitioners supervising patients with oculo-articulo-oromucocutaneous syndromes should be aware of systemic Behçet disease. Early recognition of ocular involvement is important and such patients should strongly be instructed to visit immediately an ophthalmologist, as uveitis management differs from extraocular involvements with high ocular morbidity from sight-threatening complications due to relapsing inflammatory attacks in the posterior segment of the eye. A single infliximab infusion should be considered for the control of acute panuveitis, whereas repeated long-term infliximab infusions were proved to be more effective in reducing the number of episodes in refractory uveoretinitis with faster regression and complete remission of CME.
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Affiliation(s)
- Cem Evereklioglu
- Department of Ophthalmology, Erciyes University Medical Faculty, Kayseri, Turkey
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15
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Zhao C, Yang P, He H, Lin X, Li B, Zhou H, Huang X, Kijlstra A. S-antigen specific T helper type 1 response is present in Behcet's disease. Mol Vis 2008; 14:1456-64. [PMID: 18685727 PMCID: PMC2496927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2008] [Accepted: 08/04/2008] [Indexed: 11/13/2022] Open
Abstract
PURPOSE To investigate the frequency and phenotypic and functional characteristics of S-antigen (S-Ag) specific T cells in patients with Behcet's disease (BD). METHODS Blood was taken from 23 active BD patients, 12 inactive BD patients, and 14 healthy controls. The clinical features of the patients were summarized. T cell response against 40 mixed S-Ag peptides was identified by interferon gamma (IFN-gamma) enzyme-linked immunospot assay (ELISPOT). CD69 and CD45RO were used to characterize the phenotype of S-Ag specific T cells. The functional property of S-Ag specific T cells was investigated by measuring the production of cytokines. RESULTS Response to the mixed S-Ag peptides was found in 56.5% and 25% of active and inactive BD patients, respectively. The responsiveness to S-Ag peptides was unrelated to the clinical features of the patients. About 65.8% of IFN-gamma(+) CD4(+) T cells in active BD patients expressed CD69 and CD45RO concomitantly. S-Ag peptides significantly induced a production of IFN-gamma and tumor necrosis factor (TNF)-alpha but not interleukin (IL)-2, IL-4, and IL-17 by peripheral blood mononuclear cells (PBMCs) in active BD patients with a response to S-Ag. CONCLUSIONS S-Ag specific T cells are present in certain active BD patients, and most of them are activated memory CD4(+) T cells. These T cells may be involved in the pathogenesis of BD via producing Th1-dominant cytokines.
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Affiliation(s)
- Changlin Zhao
- Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Peizeng Yang
- Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China,The First Affiliated Hospital, Chongqing Medical University, Chongqing, P. R. China
| | - Hao He
- Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xiaomin Lin
- Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Bing Li
- Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Hongyan Zhou
- Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xiangkun Huang
- Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Aize Kijlstra
- Eye Research Institute Maastricht, Department of Ophthalmology, University Hospital Maastricht, Maastricht, The Netherlands,Animal Sciences Group, Wageningen UR, The Netherlands
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16
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Clonal CD8+ TCR-Vbeta expanded populations with effector memory phenotype in Churg Strauss syndrome. Clin Immunol 2008; 128:94-102. [PMID: 18502180 DOI: 10.1016/j.clim.2008.03.505] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2007] [Revised: 03/12/2008] [Accepted: 03/17/2008] [Indexed: 11/23/2022]
Abstract
Churg Strauss Syndrome (CSS) is a systemic vasculitis in which oligoclonal T cell expansions might be involved in the pathogenesis. Combined analysis of TCR-Vbeta expression profile by flow cytometry and of TCR gene rearrangement by heteroduplex PCR was used to detect and characterize T cell expansions in 8 CSS patients, 10 asthmatics and 42 healthy subjects. In all CSS patients one or two Vbeta families were expanded among CD8+ cells, with an effector memory phenotype apt to populate tissues and inflammatory sites. Heteroduplex PCR showed the presence of one or more clonal TCR rearrangements, which reveals monoclonal or oligoclonal T cells subpopulations. After purification with a Vbeta specific monoclonal antibody, each CD8+/Vbeta+ expanded family showed a single TCR rearrangement, clearly suggestive of monoclonality. All CD8+ expansions were detectable throughout the disease course. TCR-Vbeta expanded or deleted populations were not observed in asthmatic patients. Clonal CD8+/Vbeta+ T cell expansions might be useful as a disease marker.
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17
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Atalay A, Yildiz-Demirtepe S, Tatlipinar S, Sanli-Erdoğan B, Cobankara V, Yildirim C, Bağci H, Atalay EO. HLA-B51 gene and its expression in association with Behçet’s Disease in Denizli Province of Turkey. Mol Biol Rep 2007; 35:345-9. [PMID: 17594535 DOI: 10.1007/s11033-007-9092-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2007] [Accepted: 04/30/2007] [Indexed: 11/28/2022]
Abstract
Behçet's Disease (BD) is a multisystemic inflammatory disorder as a triad of symptoms including recurrent oral and genital aphthous ulceration, and uveitis with unknown pathogenesis. Many researchers have tried to investigate the association of HLA-B51 gene with the BD. We aimed to investigate the association of the HLA-B51 gene and its expression, also polymorphic structure by PCR, RT-PCR and sequence specific oligonucleotide primers and probes in BD patients (n: 35) and control group (n: 50). According to our results, we did not observe any association in between HLA-B51 gene, its polymorphism, expression and BD patients.
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Affiliation(s)
- Ayfer Atalay
- Department of Biophysics, Medical Faculty, Pamukkale University, Denizli, Turkey.
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18
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Oztaş P, Lortlar N, Polat M, Alli N, Omeroğlu S, Basman A. Caspase-9 expression is increased in endothelial cells of active Behçet's disease patients. Int J Dermatol 2007; 46:172-6. [PMID: 17269970 DOI: 10.1111/j.1365-4632.2007.03209.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Behçet's disease is a multisystem disease of unknown etiology. Caspase-9 is responsible for initiating the caspase activation cascade during apoptosis. The aim of this study was to examine caspase-9 expression in both endothelial and perivascular infiltrates of patients with active Behçet's disease. METHODS Fifteen patients with active Behçet's disease, attending the First Dermatology Department, Ankara Numune Hospital, Ankara, Turkey between June 2003 and December 2005, were included in the study. Oral biopsy specimens from nine healthy volunteers were taken as the healthy control group, and skin biopsies from 18 psoriasis patients were used as the inflammatory control group. The specimens were examined with caspase-9 primary antibody. Statistical analyses were performed using SPSS 11.5. RESULTS The mean caspase-9-positive endothelial cell counts were 7.17 +/- 2.45 in active Behçet's disease, 4.81 +/- 0.76 in healthy controls, and 4.35 +/- 1.34 in inflammatory controls. The difference between Behçet's disease and healthy controls was statistically significant, with increased endothelial staining in active Behçet's disease (P = 0.049). The difference between Behçet's disease and inflammatory controls was also statistically significant; the rate of staining was higher in Behçet's disease (P = 0.006). The mean caspase-9-positive dermal perivascular cell counts were 5.15 +/- 2.32 in Behçet's disease, 3.32 +/- 0.82 in healthy controls, and 5.54 +/- 4.95 in inflammatory controls. These values did not show any statistically significant difference (P = 0.407). CONCLUSION Endothelial cells are one of the key cells in Behçet's disease, and our findings support the role of endothelial cells in the etiopathogenesis of Behçet's disease.
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Affiliation(s)
- Pinar Oztaş
- First Dermatology Department, Ankara Numune Education and Research Hospital, Gazi University School of Medicine, Ankara, Turkey.
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19
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Guenane H, Hartani D, Chachoua L, Lahlou-Boukoffa OS, Mazari F, Touil-Boukoffa C. [Production of Th1/Th2 cytokines and nitric oxide in Behçet's uveitis and idiopathic uveitis]. J Fr Ophtalmol 2007; 29:146-52. [PMID: 16523155 DOI: 10.1016/s0181-5512(06)73762-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION The aim of this study was to investigate the role of Th1 (IFN-gamma and IL-12), Th2 (IL-10) cytokines and nitric oxide (NO) in the immunopathologic mechanisms of uveitis related to Behçet's disease and isolated idiopathic uveitis. PATIENTS AND METHOD This study was conducted on 24 patients with Behçet's syndrome who had active uveitis, ten of whom showed isolated uveitis classified as idiopathic uveitis, and 13 healthy controls. The levels of IFN-gamma, IL-12 and IL-10 in sera and supernatants of PBMC cultures stimulated by PHA were estimated using immunoenzymatic dosage (ELISA sandwich according to the methods recommended by Immunotech France). The production of NO was measured in vivo and in vitro for the same patients using the modified Griess method. RESULTS The induction of IFN-gamma and IL-12 was higher in the two groups of patients than in the controls (P<0.001). Significant IL-10 levels were recorded in 56.5% of patients with Behçet's disease presenting uveitis versus 30% of patients with idiopathic uveitis. NO production was more pronounced in idiopathic uveitis than in Behçet's syndrome (P<0.02). CONCLUSION The predominance of the Th1 profile was associated with high production of NO in idiopathic uveitis. A Th1/Th2 profile with a moderated increase in NO production was observed in Behçet's disease. Our data have a clinical impact. The observation of combined Th1/Th2 cytokines and NO elevation in both in vivo an in vitro experiments could have a predictive value in characterizing uveitis associated with Behçet's disease.
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Affiliation(s)
- H Guenane
- Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, USTHB Bab Ezzouar, Alger, Algérie.
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20
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Gebreselassie D, Spiegel H, Vukmanović S. Sampling of major histocompatibility complex class I-associated peptidome suggests relatively looser global association of HLA-B*5101 with peptides. Hum Immunol 2006; 67:894-906. [PMID: 17145369 PMCID: PMC2269730 DOI: 10.1016/j.humimm.2006.08.294] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2006] [Revised: 07/18/2006] [Accepted: 08/17/2006] [Indexed: 12/29/2022]
Abstract
We have analyzed peptides associated with six human major histocompatibility complex (MHC) class I allomorphs expressed by the U937 cell line. Peptides were isolated by mild acid elution or by MHC class I immunoprecipitation by using W6/32 monoclonal antibody. Eighty-five peptides were sequenced by mass spectrometry, and their putative binding alleles were assigned using bioinformatic tools. Only three peptides isolated by the two approaches were identical, suggesting that the approaches may yield distinct partially overlapping peptide populations. Mild acid treatment-derived peptides manifested overall characteristics suggestive of relatively lower affinity of binding for MHC class I. Interestingly, a large proportion of putative HLA-B*5101-binding peptides was evident among the mild acid treatment-eluted peptides, and to a lesser degree in the affinity-purified peptide pool. These results suggest that HLA-B*5101 may bind a potentially large pool of peptides with relatively lower affinity. We suggest that lower affinity of peptide binding may be the basis for inefficient tolerance to HLA-B*5101-binding self-peptides, a predisposing factor for the development of Behçet disease.
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Affiliation(s)
| | | | - Stanislav Vukmanović
- Address correspondence to: Stanislav Vukmanović Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010-2970. Phone: (202) 884-3078; FAX: (202) 884-3929; e-mail:
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21
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Freysdottir J, Hussain L, Farmer I, Lau SH, Fortune F. Diversity of gammadelta T cells in patients with Behcet's disease is indicative of polyclonal activation. Oral Dis 2006; 12:271-7. [PMID: 16700735 DOI: 10.1111/j.1601-0825.2005.01185.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Behcet's disease (BD) is a multisystemic disease, with vasculitic lesions in the oral and genital mucosa, eyes, joints, skin and brain. We have previously found that gammadelta T cells are increased in peripheral blood of BD patients. The aim of this study was to investigate the extent of gammadelta T cells in oral biopsies from BD patients with special emphasis on the restriction of Vgamma and Vdelta usage. PATIENTS AND METHODS Expression of Vgamma and Vdelta chains on peripheral blood gammadelta T cells from 31 BD patients and 19 healthy controls was analysed by flow cytometry and the expression of Vgamma and Vdelta chains in nine ulcerated and eight non-ulcerated oral mucosa from BD patients and non-ulcerated oral mucosa from three healthy controls was analysed by immunohistochemistry. RESULTS Vgamma9 and Vdelta2 were the predominant chains expressed in peripheral blood of BD patients, although other Vgamma and Vdelta chains were also expressed. The presence of gammadelta T cells was only observed in the ulcerated oral mucosa but not in the non-ulcerated mucosa from the BD patients, and not in the non-ulcerated mucosa from the healthy controls. These gammadelta T cells showed no preferential expression of any of the Vgamma or Vdelta chains. CONCLUSION These data suggest a polyclonal rather than oligoclonal activation of the gammadelta T cells. This may indicate that during repeated inflammation of the oral mucosa, the gammadelta T cells are responding to a wide variety of antigenic stimuli with consequent expansion of gammadelta T cells expressing various Vgamma and Vdelta chains and that different antigenic stimuli or responses may be responsible for the clinical heterogeneity of the disease.
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Affiliation(s)
- J Freysdottir
- Department of Oral Medicine and Pathology, GKT Dental Institute, King's College, London, UK
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22
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Vallejo AN, Weyand CM, Goronzy JJ. T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection. Trends Mol Med 2004; 10:119-24. [PMID: 15102354 DOI: 10.1016/j.molmed.2004.01.002] [Citation(s) in RCA: 167] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Long-lived clonal T cells deficient in CD28 expression are commonly found in patients with inflammatory syndromes and persistent infections. Considering that CD28 loss is the most consistent immunological marker of aging, we propose that, in pathological states, CD28(null) T cells represent prematurely senescent cells resulting from persistent immune activation. These unusual lymphocytes have aberrant functions that contribute to disease-related immune abnormalities, and the degree of accumulation of CD28(null) T cells predicts the severity of clinical manifestations. We suggest that understanding of the biological properties of T cells that have reached replicative senescence will influence the future management of certain diseases. Indeed, studies on the molecular basis for the loss of CD28 are already providing information on methods to functionally rescue senescent T cells.
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Affiliation(s)
- Abbe N Vallejo
- Division of Rheumatology, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
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23
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Schaerli P, Britschgi M, Keller M, Steiner UC, Steinmann LS, Moser B, Pichler WJ. Characterization of Human T Cells That Regulate Neutrophilic Skin Inflammation. THE JOURNAL OF IMMUNOLOGY 2004; 173:2151-8. [PMID: 15265952 DOI: 10.4049/jimmunol.173.3.2151] [Citation(s) in RCA: 120] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
It is unknown whether neutrophilic inflammations can be regulated by T cells. This question was analyzed by studying acute generalized exanthematous pustulosis (AGEP), which is a severe drug hypersensitivity resulting in intraepidermal or subcorneal sterile pustules. Recently, we found that drug-specific blood and skin T cells from AGEP patients secrete high levels of the potent neutrophil-attracting chemokine IL-8/CXCL8. In this study, we characterize the phenotype and function of CXCL8-producing T cells. Supernatants from CXCL8(+) T cells were strongly chemotactic for neutrophils, CXCR1, and CXCR2 transfectants, but not for transfectants expressing CXCR4, CX3CR1, human chemokine receptor, and RDC1. Neutralization experiments indicated that chemotaxis was mainly mediated by CXCL8, but not by granulocyte chemotactic protein-2/CXCL6, epithelial cell-derived neutrophil attractant-78/CXCL5, or growth-related oncogene-alpha,beta,gamma/CXCL1,2,3. Interestingly, approximately 2.5% of CD4(+) T cells in normal peripheral blood also produced CXCL8. In addition to CXCL8, AGEP T cells produced large amounts of the monocyte/neutrophil-activating cytokine GM-CSF, and the majority released IFN-gamma and the proinflammatory cytokine TNF-alpha. Furthermore, apoptosis in neutrophils treated with conditioned medium from CXCL8(+) T cells could be reduced by 40%. In lesional skin, CXCL8(+) T cells consistently expressed the chemokine receptor CCR6, suggesting a prominent role for CCR6 in early inflammatory T cell recruitment. Finally, our data suggest that CXCL8-producing T cells facilitate skin inflammation by orchestrating neutrophilic infiltration and ensuring neutrophil survival, which leads to sterile pustular eruptions found in AGEP patients. This mechanism may be relevant for other T cell-mediated diseases with a neutrophilic inflammation such as Behçet's disease and pustular psoriasis.
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MESH Headings
- Acute Disease
- Animals
- B-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/drug effects
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CX3C Chemokine Receptor 1
- Cell Survival
- Cells, Cultured/immunology
- Cells, Cultured/metabolism
- Chemokines, CXC/analysis
- Chemokines, CXC/physiology
- Chemotaxis, Leukocyte/drug effects
- Chemotaxis, Leukocyte/physiology
- Culture Media, Conditioned/pharmacology
- Drug Eruptions/etiology
- Drug Eruptions/immunology
- Exanthema/chemically induced
- Exanthema/immunology
- Humans
- Intercellular Signaling Peptides and Proteins/analysis
- Intercellular Signaling Peptides and Proteins/physiology
- Interferon-gamma/metabolism
- Interleukin-4/metabolism
- Ionomycin/pharmacology
- Membrane Proteins/genetics
- Mice
- Neutrophils/drug effects
- Neutrophils/physiology
- Receptors, CXCR
- Receptors, CXCR4/genetics
- Receptors, Chemokine/genetics
- Receptors, G-Protein-Coupled/genetics
- Receptors, Interleukin-8A/genetics
- Receptors, Interleukin-8B/genetics
- Skin/immunology
- Skin Diseases, Vesiculobullous/chemically induced
- Skin Diseases, Vesiculobullous/immunology
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- Tetradecanoylphorbol Acetate/pharmacology
- Transfection
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
- Patrick Schaerli
- Division of Allergology, Clinic of Rheumatology and Clinical Immunology/Allergology, Inselspital, and Theodor-Kocher-Institute, University of Bern, Switzerland
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24
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Elezoglou AV, Sfikakis PP, Vaiopoulos G, Kapsimali V, Kaklamanis PG. Serum levels of soluble TNF-alpha receptor-II (P75), circulating gammadelta T-cells and Adamantiades-Behçet's disease activity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 528:261-5. [PMID: 12918703 DOI: 10.1007/0-306-48382-3_52] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Affiliation(s)
- Antonia V Elezoglou
- First Dept of Propedeutic Medicine, Laikon Hospital, Athens University Medical School, Athens, Greece
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25
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Triolo G, Accardo-Palumbo A, Dieli F, Ciccia F, Ferrante A, Giardina E, Sano CD, Licata G. Vgamma9/Vdelta2 T lymphocytes in Italian patients with Behçet's disease: evidence for expansion, and tumour necrosis factor receptor II and interleukin-12 receptor beta1 expression in active disease. Arthritis Res Ther 2003; 5:R262-8. [PMID: 12932289 PMCID: PMC193723 DOI: 10.1186/ar785] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2002] [Revised: 04/10/2003] [Accepted: 05/15/2003] [Indexed: 12/29/2022] Open
Abstract
Behçet's disease is a multisystem disease in which there is evidence of immunological dysregulation. It has been proposed that gamma/delta T cells are involved in its pathogenesis. The aim of the present study was to assess the capacity of gamma/delta T cells with phenotype Vgamma9/Vdelta2, from a group of Italian patients with Behçet's disease, to proliferate in the presence of various phosphoantigens and to express tumour necrosis factor (TNF) and IL-12 receptors. Twenty-five patients and 45 healthy individuals were studied. Vgamma9/Vdelta2 T cells were analyzed by fluorescence activated cell sorting, utilizing specific monoclonal antibodies. For the expansion of Vgamma9/Vdelta2 T cells, lymphocytes were cultured in the presence of various phosphoantigens. The expression of TNF receptor II and IL-12 receptor beta1 was evaluated with the simultaneous use of anti-TNF receptor II phycoerythrin-labelled (PE) or anti-IL-12 receptor beta1 PE and anti-Vdelta2 T-cell receptor fluorescein isothiocyanate. There was a certain hierarchy in the response of Vgamma9/Vdelta2 T cells toward the different phosphoantigens, with the highest expansion factor obtained with dimethylallyl pyrophosphate and the lowest with xylose 1P. The expansion factor was fivefold greater in patients with active disease than in those with inactive disease or in control individuals. TNF receptor II and IL-12 receptor beta1 expressions were increased in both patients and control individuals. The proportion of Vgamma9/Vdelta2 T cells bearing these receptors was raised in active disease when Vgamma9/Vdelta2 T cells were cultured in the presence of dimethylallyl pyrophosphate. These results indicate that Vgamma9/Vdelta2 T cell activation is correlated with disease progression and probably involved in the pathogenesis.
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MESH Headings
- Adult
- Behcet Syndrome/blood
- Behcet Syndrome/pathology
- Cell Division/physiology
- Cells, Cultured
- Female
- Humans
- Italy
- Lymphocyte Activation/physiology
- Male
- Middle Aged
- Phenotype
- Receptors, Antigen, T-Cell, gamma-delta/biosynthesis
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Receptors, Interleukin/biosynthesis
- Receptors, Interleukin/genetics
- Receptors, Interleukin-12
- Receptors, Tumor Necrosis Factor/biosynthesis
- Receptors, Tumor Necrosis Factor/genetics
- T-Lymphocytes/metabolism
- T-Lymphocytes/pathology
- T-Lymphocytes/physiology
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Affiliation(s)
- Giovanni Triolo
- Department of Internal Medicine, Section of Rheumatology & Clinical Immunology, University of Palermo, Palermo, Italy.
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26
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Hirohata S, Kikuchi H. Behçet's disease. Arthritis Res Ther 2003; 5:139-46. [PMID: 12723980 PMCID: PMC165051 DOI: 10.1186/ar757] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2003] [Revised: 03/06/2003] [Accepted: 03/11/2003] [Indexed: 01/24/2023] Open
Abstract
Behçet's disease is characterized by recurrent aphthous stomatitis, uveitis, genital ulcers, and skin lesions. The role of the HLA-B*51 gene has been confirmed in recent years, although its contribution to the overall genetic susceptibility to Behçet's disease was estimated to be only 19%. The production of a variety of cytokines by T cells activated with multiple antigens has been shown to play a pivotal role in the activation of neutrophils. As regards the treatment, anti-tumor necrosis factor alpha therapy has been shown to be effective for mucocutaneous symptoms as well as for sight-threatening panuveitis, although a randomized, controlled trial is required.
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Affiliation(s)
- Shunsei Hirohata
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
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27
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Bernardin F, Doukhan L, Longone-Miller A, Champagne P, Sekaly R, Delwart E. Estimate of the total number of CD8+ clonal expansions in healthy adults using a new DNA heteroduplex-tracking assay for CDR3 repertoire analysis. J Immunol Methods 2003; 274:159-75. [PMID: 12609542 DOI: 10.1016/s0022-1759(02)00514-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
A T-cell receptor heteroduplex-tracking assay (TCR-HTA) was developed to analyze the sequence diversity of the TCR beta-chain mRNA of each of the 24 T-cell receptor beta-chain variable region (TRBV). TCR-HTA allowed an estimation of the number of expanded CD8 T-cell clones whose distinct CDR3 domain mRNA made up 2% or more of the transcript of each TRBV subfamily. An average of 40 CD8+ clonal expansions (range 34-49) was detected in three healthy adults. Correct sampling of the complex mRNA transcript populations was documented by the reproducible generation of TCR-HTA patterns using independently generated PCR amplicons. The CDR3 sequence of expanded T-cell clones could be rapidly determined by direct sequencing of DNA heteroduplex bands. CD4+ and CD8+ clonal expansions were found predominantly although not exclusively in CD45RO+ CD62L- effector/memory cells and the majority of expanded T-cell clones were stable over a period of at least 6 months. Fewer CD4+ than CD8+ clonal expansions were detected in peripheral blood cells. By providing a high-resolution method for the detection of clonally expanded T-cell clones and by simplifying the pattern generated using traditional DNA heteroduplex analysis, TCR-HTA is shown to be a sensitive method for assessing levels of oligoclonality and changes in TRBV repertoires.
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Affiliation(s)
- Flavien Bernardin
- Department of Medicine, University of California, San Francisco, CA 94118, USA
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Budman C, Sarcevic A. An Unusual Case of Motor and Vocal Tics With Obsessive-Compulsive Symptoms in a Young Adult With Behcet's Syndrome. CNS Spectr 2002; 7:878-881. [PMID: 12766698 DOI: 10.1017/s1092852900022501] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Behcet's disease is a chronic relapsing-remitting, multi-system inflammatory disorder of unknown etiology, characterized by recurrent oral and genital ulcers, uveitis, and skin lesions. The most common central nervous system findings are demyelization and perivascular cell infiltration; meningoencephalitis, cerebral atrophy, and vascular thrombosis may also occur. Neuropsychiatric symptoms may include: paroxysmal dystonia, parkinsonism, delirium, hallucinations, and behavioral disturbances. We report an unusual case of explosive onset of motor and vocal tics with obsessive-compulsive symptoms in a 22-year-old male with Behcet's disease. The putative roles of infection and autoimmune mechanisms in the pathogenesis of tics and obsessive-compulsive symptoms are explored.
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Affiliation(s)
- Cathy Budman
- Department of Psychiatry and Neurology, New York University School of Medicine, New York, NY, USA
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Williams DW, Leigh J, Ramirez-Amador V, Kaonga K, Russo D, Schiødt M. Host pathogen interaction and the development of oral lesions. Oral Dis 2002; 8 Suppl 2:120-5. [PMID: 12164645 DOI: 10.1034/j.1601-0825.8.s2.2.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The aetiologies of oral ulceration, disseminated interstitial lymphocytosis syndrome and oral lymphomas have been reviewed, with emphasis on the role of HIV infection in the primary causation or modification of the presentation of these entities. There is a paucity of evidence to explain why oral ulceration is so severe in HIV infection, and why major ulceration affects the oropharynx. A number of mechanisms have been proposed to account for the development of lymphomas in patients with HIV infection, including a genetic predisposition, decreased immunosurveillance due to HIV infection, alteration of endothelial cell function and dysregulation of cytokine networks. From this review, it was concluded that there is a need for a prospective multicentre study, to elucidate the aetiological mechanisms involved in lymphomas of the oral regions in this patient group. It was concluded that, although there is anecdotal evidence implicating tobacco use in the aetiology of the lesions reviewed, this is insufficient to allow definitive statements to be made and further systematic evaluation is indicated.
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Affiliation(s)
- David W Williams
- Barts and The London, Queen Mary's School of Medicine and Dentistry, UK.
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Pennesi G, Caspi RR. Genetic control of susceptibility in clinical and experimental uveitis. Int Rev Immunol 2002; 21:67-88. [PMID: 12424837 DOI: 10.1080/08830180212059] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Giuseppina Pennesi
- Istituto Nazionale per la Ricerca sul Cancro, Centro Biotecnologie Avanzate, Genova, Italy.
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Abstract
Behçet's syndrome is a multi-system inflammatory disease affecting mainly the oral and urogenital mucosa and the uveal tract. The etiology and pathogenesis of Behçet's syndrome are unknown, but autoimmune mechanisms are implicated. We initiated this work to identify self-antigens targeted by patients with Behçet's syndrome. We used patient sera to immuno-blot tissue lysates, and we found that some patients manifest antibodies to a 37-kDa band. The 37-kDa band was detected in extracts of skin, tongue, vagina, muscle and heart but not in brain, kidney, lung, liver, intestine and thymus. In-gel digestion and mass spectrometry revealed the band to be alpha-tropomyosin. Autoimmunity to alpha-tropomyosin can be pathogenic; immunized Lewis rats developed lesions in the uveal tract and skin, with features of Behçet's disease.
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Affiliation(s)
- Felix Mor
- Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100 Israel.
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Ergun T, Ince U, Ekşioğlu-Demiralp E, Direskeneli H, Gürbüz O, Gürses L, Aker F, Akoğlu T. HSP 60 expression in mucocutaneous lesions of Behçet's disease. J Am Acad Dermatol 2001; 45:904-9. [PMID: 11712037 DOI: 10.1067/mjd.2001.117728] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Heat shock protein (60 kd HSP) has been implicated in the etiology of Behçet's disease, but its expression at sites of inflammation is unknown. OBJECTIVE Our aim was to investigate local HSP 60 expression and to quantify T-cell receptor (TCR) gamma delta-positive cells, which are known to respond to HSP peptides. METHODS Patients with active Behçet's disease (n = 21) and controls (n = 18) were included. Flow cytometric analysis was performed on peripheral blood to investigate TCR gamma delta-positive cell counts. Biopsies were performed on active skin lesions, and immunohistochemical analysis was performed by a streptavidin-biotin method using the monoclonal ML-30 antibody; HSP staining intensity and distribution were evaluated in a blinded fashion. Immunohistochemical studies were performed to quantify TCR gamma delta-positive cells at lesional sites. RESULTS Mucocutaneous lesions of patients with Behçet's disease had statistically significantly increased expression of HSP 60/65. Peripheral blood TCR gamma delta-positive cell counts were similar in both groups. However, lesional skin of patients with Behçet's disease had significantly increased gamma delta-positive T-cell counts. CONCLUSION Up-regulation of HSP expression was found at lesional skin sites in Behçet's disease. The increased number of TCR gamma delta-positive cells, which are known to respond to HSP peptides, may support the function of HSPs in the etiology of Behçet's disease. However, these findings may also be an epiphenomenon that needs to be further investigated.
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Affiliation(s)
- T Ergun
- Department of Dermatology, Marmara University School of Medicine, Istanbul, Turkey
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Affiliation(s)
- H Direskeneli
- Division of Rheumatology, Faculty of Medicine, Marmara University, Istanbul, Turkey.
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Kurhan-Yavuz S, Direskeneli H, Bozkurt N, Ozyazgan Y, Bavbek T, Kazokoglu H, Eksioglu-Demiralp E, Wildner G, Diedrichs-Möhring M, Akoglu T. Anti-MHC autoimmunity in Behçet's disease: T cell responses to an HLA-B-derived peptide cross-reactive with retinal-S antigen in patients with uveitis. Clin Exp Immunol 2000; 120:162-6. [PMID: 10759778 PMCID: PMC1905613 DOI: 10.1046/j.1365-2249.2000.01176.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Immune response to retinal autoantigens plays a central role in the pathogenesis of uveitis. A synthetic peptide (B27PD) from a common sequence of various HLA-B molecules associated with uveitis, such as HLA-B27 and 51, which shares amino acid homologies with a retinal-S antigen (S-Ag)-derived peptide (PDSAg), was shown to be immunogenic in human and experimental uveitis in the rat. In this study we investigated T cell responses to B27PD and PDSAg in patients with Behçet's disease and posterior uveitis (BD-posterior uveitis; n = 33) in comparison with non-Behçet anterior uveitis (AU, n = 14), Behçet's patients without uveitis (BD, n = 15) and healthy controls (HC, n = 32) in a 6-day proliferation assay. Patients with BD and posterior uveitis had significantly higher responses (stimulation index (SI) 2.8 +/- 1.3) than those with AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.1 +/- 0.4) and HC (SI 1.1 +/- 0.6) for B27PD (P < 0.0001). Responses to PDSAg were also higher in BD with posterior uveitis patients (SI 3.3 +/- 1.6) than AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.2 +/- 0.3) and HC (SI 1.1 +/- 0.6) (P < 0. 0001). A significant correlation between the responses to PDSAg and B27PD (r = 0.56, P < 0.001) was observed. Elevated levels of IL-2 and tumour necrosis factor-alpha were also observed in culture supernatants obtained from peripheral blood mononuclear cells after stimulation with the peptides, but no correlation was found between the proliferative responses and cytokine levels. These results suggest that cellular immunity to cross-reactive HLA-B and S-Ag-derived peptides might play a role in the pathogenesis of posterior uveitis in BD.
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Affiliation(s)
- S Kurhan-Yavuz
- Department of Rheumatology, University of Marmara, Istanbul, Turkey
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